A little over 10 years ago a series of clinical studies were published showing that untreated pain in the neonatal period (circumcision in male infants) enhanced subsequent pain responses in infancy and childhood. Basic science responded with a number of rodent studies but the majority of these studies used animals that are equivalent in age to a pre-term human infant and used inflammatory pain models. In contrast, the majority of under-treated pain in the hospital setting involves full-term infants and young children who are experiencing acute nociceptive pain. To this end, this proposal will use endothelin-1, an endogenous peptide released at sites of injury and disease, to model an acute nociceptive pain experience in a rat that is equivalent in development to a full-term human infant. We postulate that pain experience early in development decreases endothelin B receptor expression on keratinocytes in a testosterone-dependent manner. The end result of these changes is that early pain experiences sensitize males to subsequent pain. A combination of behavior, histological and pharmacological methods will be used to determine the mechanisms by which exposure to endothelin-1 early in life down-regulates the endothelin B receptor pathway. By determining the mechanism of endothelin-induced sensitization this work will lay the foundation for the development of therapeutic strategies to minimize pain and prevent pain-induced sensitization in infants and children. PUBLIC HEALTH RELEVANCE: Understanding how a pain experience early in life changes pain sensations experienced later in life is important to adequately assess pain and treat pain in infants and children. This proposal will define the mechanism by which one pain experience can enhance a subsequent pain experience. The goal of this proposal is to identify novel therapeutic targets for the development of therapies to prevent pain sensitization.